Mononuclear pterin-containing molybdenum enzymes are found in eucaryotic and procaryotic organisms and function to catalyze simple oxo-atom transfer reactions (dimethylsulfoxide reductase and sulfite oxidase families) and the oxidative hydroxylation of aldehyde and heterocyclic substrates (xanthine oxidase family), The long term objectives of the proposed research are to understand the relationship between geometric and electronic structural features of the three main pterin-containing Mo enzyme families. This is important since it is the unique electronic structures of these active sites which make specific contributions to their reactivity thus defining their role in catalysis. Recent X-ray crystallographic studies have provided detailed structural information for enzymes from each main family defining the starting point for correlating geometric structure with enzyme function. These crystallographic results have allowed for the following hypotheses to be put forth: i) the degree of saturation of the pyranopterin dithiolene C=C bond, orientation of Spp orbitals and the degree of S...S bonding character are critical factors in determining how the cyanopterin dithiolene is capable of interacting with the redox active orbital (dxy) on the Mo center, ii) the oxidation state of the pyranopterin pyrazine ring modulates electron density within the dithiolene chelate, affecting the Spp-Mo dxy orbital interaction iii) the oxo donor ligands dominate the Mo ligand field resulting in radically different bonding descriptions for dioxo ligation compared to monooxo ligation and iv) in the xanthine oxidase enzyme family the presence of a Mo=S group cis to a Mo=O group substantially affects the electronic structure of the terminal sulfido , modulating its effective electro/nucleophilicity. The proposed research relies heavily on detailed spectroscopic studies of relevant model compounds and pterin-containing Mo enzymes. The research plan will employ a combined spectroscopic approach utilizing low temperature electronic absorption, magnetic circular dichroism and resonance Raman spectroscopies to correlate spectroscopic features with geometric structure and eventually determine electronic structure contributions to reactivity. The results of the proposed research should lead to developing detailed mechanistic insight into gated electron transfer, oxygen atom transfer and the activation of C-H bonds for oxidative hydroxylation by [MoOS] units.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057378-03
Application #
6180526
Study Section
Metallobiochemistry Study Section (BMT)
Program Officer
Preusch, Peter C
Project Start
1998-06-01
Project End
2002-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
3
Fiscal Year
2000
Total Cost
$139,353
Indirect Cost
Name
University of New Mexico
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Zheng, Huayu; He, Jingxuan; Li, Jinghui et al. (2018) Generation and characterization of functional phosphoserine-incorporated neuronal nitric oxide synthase holoenzyme. J Biol Inorg Chem :
Krausze, Joern; Hercher, Thomas W; Zwerschke, Dagmar et al. (2018) The functional principle of eukaryotic molybdenum insertases. Biochem J 475:1739-1753
Yang, Jing; Dong, Chao; Kirk, Martin L (2017) Xanthine oxidase-product complexes probe the importance of substrate/product orientation along the reaction coordinate. Dalton Trans 46:13242-13250
Kirk, Martin L (2017) Designed metalloenediyne warheads damage DNA and outpace DNA polymerase. Proc Natl Acad Sci U S A 114:9497-9499
Sugimoto, Hideki; Sato, Masanori; Asano, Kaori et al. (2016) A Model for the Active-Site Formation Process in DMSO Reductase Family Molybdenum Enzymes Involving Oxido-Alcoholato and Oxido-Thiolato Molybdenum(VI) Core Structures. Inorg Chem 55:1542-50
Yang, Jing; Mogesa, Benjamin; Basu, Partha et al. (2016) Large Ligand Folding Distortion in an Oxomolybdenum Donor-Acceptor Complex. Inorg Chem 55:785-93
Stein, Benjamin W; Kirk, Martin L (2015) Electronic structure contributions to reactivity in xanthine oxidase family enzymes. J Biol Inorg Chem 20:183-94
Brines, Lisa M; Coggins, Michael K; Poon, Penny Chaau Yan et al. (2015) Water-soluble Fe(II)-H2O complex with a weak O-H bond transfers a hydrogen atom via an observable monomeric Fe(III)-OH. J Am Chem Soc 137:2253-64
Yang, Jing; Giles, Logan J; Ruppelt, Christian et al. (2015) Oxyl and hydroxyl radical transfer in mitochondrial amidoxime reducing component-catalyzed nitrite reduction. J Am Chem Soc 137:5276-9
Stein, Benjamin W; Kirk, Martin L (2014) Orbital contributions to CO oxidation in Mo-Cu carbon monoxide dehydrogenase. Chem Commun (Camb) 50:1104-6

Showing the most recent 10 out of 57 publications